编码 KRAS、HRAS 和 NRAS 的 RAS 基因是导致癌症死亡的三种最常见突变癌基因。肿瘤发生是 RAS GTPases 失调的最重要结果之一。尽管这些结构已被广泛研究，但关于这三种亚型的实际结合构象，尤其是突变时，仍有更多待发现，以设计抑制药物。最近的研究已经确定了三种亚型之间的重要相互作用，当其他亚型发生突变时，这些相互作用会影响其他亚型的致癌强度。在本研究中，我们利用分子动力学模拟来检查 KRAS 单独相互作用以及与 HRAS 和 NRAS 相互作用时结构特性、机制和动能的变化。值得注意的是，我们发现，与 WT-NRAS 相比，WT-KRAS 与 WT-HRAS 结合时的方向旋转了 180°，突变体表现出类似的结合模式。亚型与 KRAS 的结合位点与涉及 GDP/GTP 活性位点和 KRAS 二聚化位点的结合位点具有相似性。因此，异构体相互作用可以作为 KRAS 作用的抑制方法。这项研究通过最近发现的一种新的亚型相互作用方法，增进了对抑制 RAS 驱动的癌症的理解，该方法已被证明是一种有效的替代治疗方法。我们开发了相互作用的蓝图，这将有利于开发模拟同工型相互作用的 KRAS 突变体特异性和泛 KRAS 突变体抑制药物。我们的结果支持突变体 KRAS 在与 WT-HRAS 和 WT-NRAS 结合时通过亚型的高变区与 KRAS G 结构域结合的直接相互作用抑制机制。此外，我们的结果支持通过改变异构体的浓度或基于整体结构和动力学稳定性以及突变体异构体复合物的结合强度的药物替代品来减少致癌 KRAS 的影响的方法。版权所有 © 2024西尔弗曼、格伯、谢克维奇、斯坦因、西格曼、戈埃尔和迈特拉。

The RAS genes which code for KRAS, HRAS, and NRAS are three of the most frequently mutated oncogenes responsible for cancer deaths. Tumorigenesis is one of the most significant outcomes of deregulation of RAS GTPases. Although the structures have been extensively studied, there is still more to be discovered about the actual binding conformations of the three isoforms, especially when mutated, to design an inhibitory drug. Recent studies have identified important interactions between the three isoforms that affect the oncogenic strength of the others when they are mutated. In this study, we utilize molecular dynamics simulations to examine the modifications of the structural property, mechanism, and kinetic energy of KRAS when interacting individually and with HRAS and NRAS. Notably, we found that WT-KRAS' orientation when bound to WT-HRAS vs. WT-NRAS is rotated 180°, with mutants demonstrating a similar binding pattern. The binding sites of the isoforms with KRAS share similarities with those involved in the GDP/GTP active site and site of KRAS dimerization. Thus, the isoform interaction can serve as an inhibitory method of KRAS actions. This study advances the understanding of inhibiting RAS-driven cancers through a novel isoform interaction approach only recently discovered, which has been proven to be an effective alternate therapeutic approach. We developed a blueprint of the interaction which would be beneficial in the development of KRAS mutant-specific and pan-KRAS mutant inhibitory drugs that mimic the isoform interactions. Our results support the direct interaction inhibition mechanism of mutant KRAS when bound to WT-HRAS and WT-NRAS by the isoforms' hypervariable region binding to the G-domain of KRAS. Furthermore, our results support the approach of reducing the effects of oncogenic KRAS by altering the concentration of the isoforms or a drug alternative based on the overall structural and kinetic stability, as well as the binding strength of the mutant-isoform complexes.Copyright © 2024 Silverman, Gerber, Shaykevich, Stein, Siegman, Goel and Maitra.